This invention relates to therapeutic compositions for use in treating diseases of connective tissues in animals, more particularly, for use in treating osteoarthritis in mammals, such as humans, dogs, cats, pigs, horses, cows, goats and sheep.
Arthritic diseases, characterized by the pain, inflammation and stiffness of the joints leading to reduced range of mobility, are due to the degradation of connective tissue (mainly cartilage) in joints. Such diseases particularly affect weight-bearing joints such as the hips, knees, spine, ankles and feet and those joints with frequent movement such as hands, arms and neck.
Osteoarthritis (OA) in particular is a degenerative disease of the joint cartilage resulting in narrowing of the joint space and changes in the underlying bone (Barclay, et al., The Annals of Pharmacotherapy, (May, 1998) 32: 574-79). OA is the most common form of arthritis among people and it affects approximately one in ten people in North America. People of all ages can get OA, but it more often affects older people and women. For example, 85% of the age group 70 years or older is affected by OA (The Arthritis Society website, (http://www.arthritis.ca), Feb. 4, 2000, published by The Arthritis Society). OA is not limited to humans, but occurs in other mammals such as horses, dogs, cats, mice and guinea pigs as well, making OA one of the most common sources of chronic pain seen by veterinarians.
The cause of OA could be one or more of the following: nutritional deficiencies, aging, long-term stress on joints (e.g. athletes, manual workers), old joint injuries and genetic factors. The tissue that is directly affected is the cartilage covering the end of long bones in joints that provide cushioning for the bones during movements. In normal cartilage, chondrocytes (cartilage cells) maintain a balance between the synthesis and degradation of cartilage matrix. However, when the degradation of cartilage matrix exceeds that of synthesis, it leads to OA. When the disease progresses further, bone underlying the articular cartilage in joints becomes exposed in certain places. In addition, irregular bone growth occurs in the place of degenerating cartilage resulting in rough bony alterations. As a result, the joint loses its smooth functioning leading to joint pain, stiffness and swelling thus limiting mobility.
Cartilage is a unique tissue having cells (chondrocytes) embedded in their own secretions which forms the cartilage matrix. The cartilage matrix is composed of a meshwork of collagen fibrils and proteoglycan aggregates filling the space between collagen. Collagen fibrils provide high tensile strength and proteoglycan aggregates provide internal swelling pressure due to their hydrophilic nature. Cartilage cells are remarkable in that they have the ability to proliferate while synthesizing and remodeling the matrix around them. These two features provide the cartilage the ability to repair itself during damage and replenish wear and tear.
Collagen fibrils are a major component of the cartilage matrix. Collagen is made from amino acids, particularly lysine, proline and glycine. Fibrillar collagens are triple helical molecules. The three xcex1-chains of each collagen molecule are initially produced as individual peptides which are further processed by the hydroxylation of proline and lysine residues bound to the peptides. The hydroxyproline and hydroxylysine so produced facilitate hydrogen bonding between the three xcex1-chains, this being essential for the formation of the triple helical structure (Linsenmayer, Collagen, Chapter 1 in Cell Biology of Extracellular Matrix, Second Edition, Elizabeth D. Hay, ed., Plenum Press, N.Y. (1991) pp. 7-13). Unlike individual collagen peptides (xcex1-chains) that become easily digested by proteolytic enzymes, triple helical collagen is extremely stable to proteolytic enzymes, heat and variations of pH. Therefore, the most important step in collagen synthesis is the formation of the triple helical structure by hydroxylation of amino acids in collagen xcex1-chains. While the Linsenmayer reference suggests that ascorbic acid and ferrous ions are cofactors in the hydroxylation of proline and lysine to hydroxyproline and hydroxylysine respectively, Linsenmayer does not suggest that a therapeutic composition comprising ascorbic acid and ferrous ions would be useful in the treatment of osteoarthritis.
Proteoglycan aggregates are the other major component of the cartilage matrix. Cartilage proteoglycans are macromolecules comprised of glycosaminoglycan (GAG) chains, such as chondroitin sulphate and keratan sulphate, that are made up of repeating disaccharide units containing aminosugars, attached to a core protein. Proteoglycans are in turn attached to a backbone of hyaluronic acid, which is yet another GAG. Among GAGs of cartilage, hyaluronic acid is unique in that it is an extremely large molecule with about 25,000 repeating disaccharide units (in comparison, chondroitin sulphate and keratan sulphate have only about 250 and 80 repeating disaccharide units respectively). About 50% of hyaluronic acid and keratan sulphate are glucosamine.
Rheumatoid arthritis (RA) is a disease that has some similar symptoms to osteoarthritis, but whose cause is considerably different. RA is known to be an autoimmune disease (Maini, et al., Aetiopathogenesis of Rheumatoid Arthritis. in Mechanisms and Modes of Rheumatoid Arthritis, (1995) Academic Press Ltd. pp. 25-46), in which the immune system attacks body tissues as if they were foreign invaders, culminating in inflammatory and destructive responses in joints as well as other tissues. Although the exact cause of RA is not completely understood, contributing factors are believed to include food allergies, pathogens, leaky gut syndrome and hereditary factors. Because of the difference in cause of RA as opposed to diseases of the connective tissues such as osteoarthritis, it is not necessarily expected that treatment for RA would be effective against osteoarthritis and the like.
A number of treatments for osteoarthritis and like diseases are commonly used. Most of the treatments currently available are aimed towards reducing symptoms but do not deal with the underlying tissue degradation. The use of steroids, corticosteroids and other anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin(trademark), relieve symptoms and reduce pain but also do not deal with the underlying tissue degeneration. NSAIDs may even speed up the progression of OA (Rashad et al., The Lancet, (September, 1989) 2: 519-521, and, Herman et al., The Journal of Rheumatology, (1986) 13: 1014-1018).
Therapies based on the regeneration of connective tissue, particularly cartilage, are attractive long-term solutions to the problem of osteoarthritis. To this end, there have been a number of disclosures of therapeutic compositions for the treatment of arthritic diseases.
U.S. Pat. Ser. No. 3,683,076 issued on Aug. 8, 1972 to Rovati discloses pharmaceutical compositions comprising the glucosamine saltsxe2x80x94glucosamine sulphate and glucosamine hydroiodidexe2x80x94for the treatment of osteoarthritis and rheumatoid arthritis.
U.S. Pat. Ser. No. 5,587,363 issued on Dec. 24, 1996 to Henderson discloses therapeutic compositions comprising a synergistic combination of certain aminosugars (glucosamine and its salts) with GAG""s (chondroitin and its salts) for the repair and replacement of connective tissue. Henderson suggests that Zn, Mn and Vitamin C play a role in the synthesis of procollagen which is a building block of collagen and that Cu, Fe and Vitamin C play a role in the synthesis of collagen from procollagen. However, Henderson does not disclose synergistic compositions of ferrous ion and an ascorbate. Henderson further suggests that glucosamine is a building block in the synthesis of procollagen and that procollagen is a building block in proteoglycan synthesis. However, it is generally accepted that glucosamine is not a building block of procollagen, but is a building block of proteoglycan, while amino acids are the building blocks of procollagen which becomes further processed to give rise to collagen.
Great Britain application Serial Number 2,317,109 published on Mar. 16, 1998 discloses a therapeutic composition for the treatment and repair of connective tissue in mammals comprising glucosamine, chondroitin sulphate and one or both of ascorbic acid and zinc sulphate. This application teaches that ascorbic acid and zinc sulphate serve as catalysts in the metabolic pathways whereby cartilage and related tissues are produced from the chondroitin sulphate and glucosamine building blocks. It further teaches that one of ascorbic acid and zinc sulphate may be omitted from the composition. This application does not teach a role for ascorbic acid and ferrous ion in the production of collagen nor does it teach a synergistic combination of ferrous ion and ascorbic acid in the production of connective tissue.
Barclay (Barclay, et al., The Annals of Pharmacotherapy, (May, 1998) 32: 574-79) teaches the use of glucosamine derivatives, such as the sulphate, hydrochloride and chlorhydrate salts as well as N-acetylglucosamine, for the treatment of osteoarthritis. Barclay suggests that glucosamine can be used in combination with herbs, vitamins and minerals including the salts of magnesium, potassium, copper, zinc and selenium and vitamins A and C. There is no disclosure of a therapeutic combination of ferrous ion and ascorbic acid.
Levenson (Levenson, G. E., Experimental Cell Research, (1969) 55: 225-228) teaches the effect of ascorbic acid on chondrocytes. Levenson suggests that ascorbic acid plays a role in the production of cartilaginous material but does not disclose a combination of ascorbic acid and ferrous ion.
Deal (Deal and Moskowitz, Rheum. Dis. Clin. North. Am., (May, 1999) 25(2): 379-95) discloses nutraceuticals as therapeutic agents in osteoarthritis comprising glucosamine and chondroitin sulphate. Glucosamine derivatives have been shown to be as effective as NSAIDs in relieving the symptoms of OA without having the adverse side effects of NSAIDs.
Sandy (Sandy, et al., Biochem. J., (1998) 335: 59-66) discloses the inhibitory effect of glucosamine on aggrecanase, an enzyme that breaks down aggrecan in cartilage. Test formulations also contain ascorbic acid but there is no discussion of its role. Sandy does not teach the combination of ferrous ion and ascorbic acid in a therapeutic composition for the treatment of osteoarthritis.
European Patent Serial Number 25,721 published on Mar. 25, 1981 discloses an oral medication for the treatment of rheumatoid arthritis comprising a mixture of a variety of metals including ferrous ions in the form of ferrous sulphate. There is no discussion of the role of ferrous ions, nor is there any suggestion that ascorbic acid may be used in combination, nor is there any indication that the medication is effective against diseases of the connective tissue such as osteoarthritis. As has been discussed previously, rheumatoid arthritis is a different disease and it is not necessarily expected that medications useful against rheumatoid arthritis would be effective against diseases like osteoarthritis.
While the aforementioned compositions have been successful to varying degrees, none have proven to be entirely satisfactory in the treatment of diseases of the connective tissue like osteoarthritis. In particular, there is still a need for therapeutic compositions that further facilitate the production of collagen alone or in combination with the production of GAGs.
The disclosures of all previously mentioned patents, patent applications and non-patent references are hereby incorporated by reference to the extent that they are compatible with this application.
It is therefore an object of this invention to provide compositions and methods useful in treating a disease of connective tissue, particularly osteoarthritis, in animals, preferably mammals, more preferably humans, dogs, cats, pigs, horses, cows, goats and sheep.
It has now been found that a combination of ferrous ion and an ascorbate is surprisingly effective at facilitating the production of connective tissue and is thus useful in treating diseases of connective tissue. It has also been found that a glucosamine derivative in combination with ferrous ion and an ascorbate is even more surprisingly effective.
In accordance with the teachings of the present invention, there is provided a composition for treating a disease of connective tissue comprising a therapeutically effective amount of ferrous ion and a therapeutically effective amount of an ascorbate.
There is also provided a composition for treating a disease of connective tissue comprising a therapeutically effective amount of ferrous ion, a therapeutically effective amount of an ascorbate and a therapeutically effective amount of a glucosamine derivative.
There is still further provided a use of a composition comprising a therapeutically effective amount of ferrous ion and a therapeutically effective amount of an ascorbate for treating a disease of connective tissue. The use of ferrous ion and ascorbate may be in combination with a therapeutically effective amount of a glucosamine derivative.
There is still further provided a use of a therapeutically effective amount of ferrous ion and a therapeutically effective amount of an ascorbate for preparing a medicament for treating a disease of connective tissue. The use of ferrous ion and ascorbate may be in combination with a therapeutically effective amount of a glucosamine derivative.
There is yet still further provided a method of treating a disease of connective tissue comprising administering to a patient suffering from the disease, a composition comprising a therapeutically effective amount of ferrous ion and a therapeutically effective amount of an ascorbate. The administration of ferrous ion and ascorbate may also be in combination with the administration of a therapeutically effective amount of a glucosamine derivative.
The compositions of the present invention comprise ferrous ion and an ascorbate which, surprisingly, act synergistically in the development of cartilage. Without being limited to any particular mode of action, it is thought that the ferrous ion and the ascorbate influence the production of collagen.
While it is thought that ascorbate and ferrous ion enhance cartilage development by enhancing collagen synthesis, it is thought that glucosamine is a building block for glycosaminoglycans of proteoglycans in the cartilage matrix. The presence of the two types of cartilage enhancing agents further enhances total cartilage development. The addition of a glucosamine derivative to the ferrous ion/ascorbate composition provides a further enhanced effect on activity.
The term xe2x80x9ctreatingxe2x80x9d is used in a broad sense to encompass the amelioration of both the cause and the symptoms of a preexisting disease or condition, and the prevention or prophylaxis of the disease or condition.
Ferrous ions are preferably provided in the form of an inorganic or organic acid salt wherein the ferrous ion is accompanied by a counter-ion to balance the charge. Examples of inorganic counter-ions are sulphate, phosphate, nitrate, carbonate and halide. A preferred inorganic counter-ion is sulphate. Ferrous sulphate is a preferred inorganic form for ferrous ion. Examples of organic counter-ions are fumarate, gluconate, ascorbate, tartarate, succinate, lactate, citrate and maleate. Three preferred organic counter-ions are fumarate, ascorbate and gluconate. Ferrous fumarate, ferrous ascorbate and ferrous gluconate are three preferred organic forms for ferrous ion. Ferrous ascorbate has the advantage of providing both ferrous ion and ascorbate in the same compound.
Ferrous ion is present in the composition in an amount effective for promoting the development of connective tissue in the body. The actual amount is not critical provided it is sufficient to promote such development. The daily dosage of ferrous ion is preferably in the range of about 0.5 mg to about 200 mg, more preferably in the range of about 2 mg to about 200 mg, yet more preferably in the range of about 10 mg to about 18 mg, and most preferably is about 15 mg.
An ascorbate is any species capable of providing the ascorbate ion. Examples include ascorbic acid (Vitamin C) and salts of ascorbic acid including the potassium, sodium, calcium, ferrous and manganese salt. Ascorbic acid, calcium ascorbate and ferrous ascorbate are preferred. Ascorbic acid is the more preferred ascorbate.
Ascorbate is present in the composition in an amount effective for promoting the development of connective tissue in the body. The actual amount is not critical provided it is sufficient to promote such development. The daily dosage is preferably in the range of about 40 mg to about 1000 mg, more preferably in the range of about 40 mg to about 500 mg or about 100 mg to about 1000 mg, and most preferably is about 100 mg.
Glucosamine is an aminosugar. Examples of glucosamine derivatives are glucosamine itself, glucosamine hydrochloride, glucosamine hydroiodide, glucosamine chlorhydrate, glucosamine sulphate and N-acetyl glucosamine. Glucosamine hydrochloride and glucosamine sulphate are preferred glucosamine derivatives.
The glucosamine derivative is present in the composition in an amount effective for promoting the development of connective tissue in the body. The actual amount is not critical provided it is sufficient to promote such development. The daily dosage is preferably in the range of about 500 mg to about 3000 mg, more preferably in the range of about 1000 mg to about 2000 mg, and most preferably is about 1500 mg.
In a particularly preferred embodiment, the composition consists essentially of an effective amount of ferrous ion, an effective amount of an ascorbate and an effective amount of a glucosamine derivative. Especially preferred is a composition consisting essentially of an effective amount of ferrous sulphate, ferrous ascorbate or ferrous fumarate, an effective amount of ascorbic acid and an effective amount of glucosamine hydrochloride or glucosamine sulphate.
The dosage ranges described above are typically for humans. One skilled in the art can readily determine appropriate doses for other animals.
The compositions of the present invention may also include other factors that may be useful in treating a disease of connective tissue. These include glycosaminoglycans (GAGs) such as chondroitin.
Other minerals and vitamins which have other therapeutic indications may be present in the compositions. These include: zinc (in the form of zinc sulphate for example), potassium, sodium, calcium, magnesium, vitamin D and vitamin E.
The compositions are preferably formulated together with a pharmaceutically acceptable excipient or diluent. Such excipients or diluents as well as the methods of formulating the compositions are well known to those skilled in the art. Cellulose, maltodextrin and water are preferred.
In another particularly preferred embodiment, the composition consists essentially of an effective amount of ferrous ion, an effective amount of an ascorbate, an effective amount of a glucosamine derivative and a pharmaceutically acceptable excipient or diluent. Especially preferred is a composition consisting essentially of an effective amount of ferrous sulphate, ferrous ascorbate or ferrous fumarate, an effective amount of ascorbic acid, an effective amount of glucosamine hydrochloride or glucosamine sulphate, and water, cellulose or maltodextrin.
The compositions are generally formulated in a dosage form. Dosage forms include powders, tablets, capsules, solutions, suspensions, emulsions and other forms that are readily appreciated by one skilled in the art. The compositions may be administered orally, parenterally, intravenously or by any other convenient method. Capsules and tablets for oral administration are preferred.
The compositions of the present invention may also be admixed with a food or beverage and taken orally in such a manner. Foods or beverages may help mask the flavour of ferrous ion thus making the composition more palatable for consumption by humans or other animals. Fortified foods and beverages may be made by adding the composition of the present invention during the manufacturing of the food or beverage. Alternatively, the consumer may add the composition to the food or beverage near the time of consumption. Each ingredient of the composition may be added to the food or beverage together with the other ingredients or separately from the other ingredients. Examples of foods and beverages are cereals, snack bars, dairy products, fruit juices, powdered food and dry powder beverage mixes.
There is also provided a method for treating a disease of connective tissue, such as osteoarthritis, comprising administering a composition comprising an effective amount of ferrous ion and an effective amount of an ascorbate to a patient suffering from the disease. The method may further comprise administering the composition further including an effective amount of a glucosamine derivative.
In such methods, the patient preferably receives from about 0.5 mg to about 200 mg (more preferably from about 2 mg to about 200 mg) of ferrous ion per day and from about 40 mg to about 1000 mg of the ascorbate per day. More preferably, the patient receives from about 10 mg to about 18 mg of ferrous ion per day and from about 100 mg to about 1000 mg (or from about 40 mg to about 500 mg) of the ascorbate per day. When a glucosamine derivative is also administered, it is preferably administered in an amount from about 500 mg to about 3000 mg per day, more preferably in an amount from about 1000 mg to about 2000 mg per day.
One skilled in the art will understand that, in a method for treating diseases of connective tissue, daily dosage can be given all at once in a single dose or can be given incrementally in several smaller dosages. Thus, the compositions of the present invention can be formulated such that the recommended daily dose is achieved by the administration of a single dose or by the administration of several smaller doses.
It is apparent to one skilled in the art that the compositions of this invention can be included in a commercial package together with instructions for its use against a disease of connective tissue, such as osteoarthritis. Such a package may be in the form of a sachet, bottle or blisterpack but is not limited to such. Instructions are normally in the form of a written material but are not limited to such.